Prognostic prediction of preoperative nutritional status in low-grade appendiceal mucinous neoplasms

To describe the preoperative nutritional status of Low-grade Appendiceal Mucinous Neoplasms (LAMNs) and identify prognostic factors for survival. Medical records from 165 patients with LAMNs who attended the Aerospace Center Hospital, Beijing, China between January 2017, and December 2018 were retrospectively reviewed. Survival analysis was performed with the Kaplan–Meier method, the log-rank test, and a Cox proportional hazards model. Among 165 patients, 59 (36%) were male and 106 (64%) were female. Patient’s median age was 58 years (range 20 to 78 years). Univariate analysis indicated that gender, weight loss, prior surgical score (PSS), red blood cell, albumin, peritoneal cancer index (PCI), completeness of cytoreduction (CCR), and hyperthermic intraperitoneal chemotherapy (HIPEC) were related to prognosis. Multivariate analysis showed that PSS, CCR and HIPEC were independent predictors of prognosis. The preoperative nutritional status of patients plays an important role in predicting prognosis. Patients can benefit from a complete cytoreductive surgery (CCRS) and HIPEC in an experienced institution for the first medical treatment.

Study parameters. The analysis included the following clinicopathological parameters: gender, age, intestinal obstruction, weight loss, prior surgical score (PSS), red blood cell (RBC), hemoglobin (Hb), albumin (ALB), hospitalization, right hemicolectomy, intraoperative peritoneal cancer index (PCI), completeness of cytoreduction (CCR), operation time, blood loss volume, intraoperative RBC transfusion volume, intraoperative plasma transfusion volume, intraoperative HIPEC, and follow-up time. We obtained cutoff values based on objective data for gender, intestinal obstruction, weight loss, PSS, RBC, Hb, ALB, right hemicolectomy and HIPEC, among which the cutoff values for Hb and ALB were based on the lower limit of the normal reference range. The cutoff values of age, PCI, and CCR were obtained according to the previous grouping of our research center [5][6][7][8] . Due to the wide range of hospitalization days, we selected one month as the cutoff value. We used 1000 ml as the cutoff value of blood loss according to the indication for blood transfusion. We used the median to obtain cutoff values for operation time, intraoperative RBC and plasma transfusion volume.
Among these characteristics, PSS was scored on a scale from 0 to 3, where PSS-0 was no surgery or biopsy had been performed for cancer, PSS-1 was surgery had been performed in one abdominal region, PSS-2 was surgery had been performed in two to five regions, and PSS-3 was surgery had been performed in > 5 regions 9 . The PCI was determined intraoperatively where neoplasm volume and extent of peritoneal dissemination in each of 13 abdominopelvic regions (nine anatomical regions in the abdomen and four segments in the small bowel) were scored on a scale from 0 to 3 and summed 4 . Residual disease following CRS was scored according to the CCR on a scale from 0 to 3, where CCR-0 was no macroscopic residual cancer remained, CCR-1 was residual neoplasm nodules < 2.5 mm remained, CCR-2 was nodules between 2.5 mm and 2.5 cm remained, and CCR-3 was persistent neoplasm nodules > 2.5 cm remained 10 . Overall survival (OS) was calculated from the date of first CRS and HIPEC to the time of death or the last follow-up.
Follow-up. The patients were reexamined every 6 months, including abdominopelvic enhanced CT and tumor markers. The follow-up method was telephone and or reexamine. The follow-up time was from the date of first surgical diagnosis to June 2020, and OS was counted. All patients were followed up. Statistical analysis. Statistical analyses were conducted using SPSS version 20 (SPSS, Chicago, Illinois, USA). Continuous data are presented as medians and range. Categorical data are presented as number and percentages. Univariate survival analysis was performed with the Kaplan-Meier method and the log-rank test. Statistically significant variables were included in a multivariate analysis, which used a Cox proportional hazards model to identify independent prognostic factors for survival. All live patients were censored. P < 0.05 was considered statistically significant.

Prognostic factors analysis.
Prognostic factors for OS on univariate analysis are presented in Table 2.

Discussion
In 2016, the Peritoneal Surface Oncology Group International (PSOGI) classified appendiceal mucinous neoplasms into four categories: low-grade appendiceal mucinous neoplasms (LAMNs), high-grade appendiceal mucinous neoplasms (HAMNs), Mucinous adenocarcinoma (MAC) and mucinous adenocarcinoma with signet ring cells (MAC-S) 11 . Their definition on appendiceal mucinous epithelia are regarded as a milestone 12 . All patients included in this study were pathologically confirmed as low-grade mucinous neoplasms of appendiceal origin. In order to avoid the possible outcome bias caused by pathological types, this study only analyzed the characteristics of patients with the most common LAMNs.
This study described the perioperative risk factors affecting the prognosis of LAMNs and identified the independent predictors of OS. From January 2017 to December 2018, 235 patients with appendiceal mucinous neoplasms underwent surgery in Aerospace Center Hospital, Beijing, China. PMP is a clinical syndrome characterized by "jelly like" neoplasms formed by mucinous neoplasms implanted on the surface of surrounding organs. PMP mainly originates from the appendix, which is consistent with other studies 13 . Our study was designed according to different pathological types, of which 165 patients were included in our analysis.
Our center is one of the major centers for the treatment of pseudomyxoma peritonei in China. Due to China's large population base, the number of people suffering from this disease is relatively large. But many patients do not have their first operation in our center when they are diagnosed. The most patients had a large neoplasm load and were located in the middle or late stage of the disease when sought medical advice. The median PCI score was 32 (range, 0 to 39) which was the reason for the low radical rate, and the complete CRS was maintained at about 30%. Although univariate analysis showed that PCI could predict prognosis, it was not an independent predictor of OS after CRS and HIPEC. On the contrary, CCR can be used as an independent predictor of OS after CRS and HIPEC, suggesting that patients will benefit from reaching CCR 0-1. However, whether the right hemicolectomy was removed or not, operation time, blood loss volume, intraoperative RBC infusion volume or plasma volume and length of hospital stay could not predict postoperative survival. Despite this, we recommend that a definitive follow-up schedule be formulated after CRS and HIPEC to detect recurrence and plan subsequent treatment.
We scored the prior surgical outcomes with PSS for each patient; PSS-0 was the rating for no surgery or biopsy, PSS-1 for surgery in one abdominal region only, PSS-2 for surgery in two to five regions, and PSS-3 for surgery in more than five regions 5 . A recent report showed that the univariate analysis of poor prognosis in patients with peritoneal pseudomyxoma after neoplasm reduction included women (P = 0.0127), intestinal obstruction before treatment (P = 0.00791) and PSS (P = 0.0054). There was also a significant difference in PSS in multivariate analysis (P = 0.0041) 14 . Our results suggested that male postoperative survival was worse, but it was not an independent factor for the prognosis. We have not confirmed that intestinal obstruction before surgery was related to postoperative survival, which may be relevant to most of the selected cases were incomplete intestinal obstruction. Our results also showed that PSS can be used as an independent predictor of OS after CRS and HIPEC, suggesting that the more times of operations, the poorer prognosis. On the contrary, patients can benefit from the first diagnosis and treatment to an experienced institution to complete the maximum degree of neoplasm reduction surgery.
We creatively studied the general indicators of preoperative nutritional status, including weight loss, erythrocyte count, anemia and ALB, and analyzed the relationship between them and postoperative survival. Univariate analysis showed that weight loss, RBC count decrease and ALB decrease were related to poor postoperative survival, but they were not independent predictors, indicating that the general state of patients before operation was closely related to the prognosis. Anemia had nothing to do with postoperative survival, which may be related to our sufficient blood transfusion, and it also showed that RBC can better predict postoperative survival than hemoglobin. A study of modified Glasgow Prognostic Score (mGPS) predicting survival after complete CRS and HIPEC in patients with appendiceal peritoneal pseudomyxoma. The mGPS for each patient was calculated using the C-reactive protein (CRP) and albumin levels 15  www.nature.com/scientificreports/ without elevation of CRP (≤ 10 mg/L) are classified as mGPS-0 regardless of their albumin level. Patients with elevated CRP levels > 10 mg/L and normal albumin are classified as mGPS-1, and patients with elevated CRP and hypoalbuminaemia (< 35 g/L), are classified as mGPS-2 16 . The results showed that the long-term survival rate decreased along with the increase of mGPS 17 . This also indirectly reflects the value of albumin in predicting postoperative survival of patients with PMP. The combination of CRS and HIPEC is recognized as the gold standard treatment for appendix derived PMP 18 . One study showed that higher PCI predicted lower progression free survival in patients with appendiceal PMP, and the impact of PCI remained an important prognostic variable in patients with low-grade appendiceal pseudomyxoma and appendiceal adenocarcinoma 9 . The study also demonstrated that a higher CCR score (CCR-2 or CCR-3) was associated with significantly worse 5-year survival (24%), compared with 85% in patients with CCR-0 and 80% in patients with CCR-1. In our study, through univariate analysis, CCR (2/3 vs. 0/1) and PCI (≥ 20 vs. < 20) were the prognostic factors of OS in LAMNs patients. We have reason to assume that early detection, early treatment and maximum cell reduction will achieve better long-term survival. Another multicenter cohort study analyzed 1924 patients with PMP due to an appendiceal mucinous neoplasm. Their results showed that compared with the CRS-alone group, the CRS-HIPEC group had better 5-year overall survival in all subsets, including CC-2/3 (16.1% [95% CI 10.4-24.8%] vs 28.4% [95% CI 19.6-41.1%]; P = 0.007) 19 . Our study also showed that with or without HIPEC was an independent prognostic factor of LAMNs, suggesting that patients will benefit from HIPEC on the premise that they can tolerate HIPEC.

Conclusions
In conclusions, this study systematically analyzes of the prognostic factors of perioperative LAMNs patients, especially the analysis of some preoperative indicators that reflect the general condition of patients. It is innovative compared with the previous studies. PSS and CCR can be used as independent predictors of the prognosis of LAMNs patients, which provide a theoretical basis for judging the prognosis of patients before clinical operation, and also draw the importance of complete CRS in an experienced institution for the first medical treatment. However, other pathological types and prospective studies need to further verify the situation for patients.

Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.